While the control of feeding and the homeostatic regulation of food intake are modulated by hypothalamic neuropeptides including orexin, ghrelin and leptin, the hedonic value of food is regulated by the mesolimbic dopamine (DA) system (Kenny, 2011; Volkow et al., 2011). Similar to drugs of abuse, DA has been shown to be involved in the reinforcing effects of food (Comings and Blum, 2000) by acting on the DAergic projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) (Wise, 2006). For example, initial food intake causes DA release in the dorsal striatum and the degree of pleasure from eating correlates with the amount of DA release (Small et al., 2003; Szczypka et al., 2001). Conversely, after an extended period of highly palatable food consumption, many studies have found decreases in basal and evoked DA release as well as decreases in DA D2 (D2R) receptor expression in the NAc and dorsal striatum in both animal models and in obese human subjects (reviewed in (Kenny, 2011; Volkow et al., 2011)). Interestingly, similar DAergic signaling deficits have been observed in animals withdrawn from long-term ethanol exposure and in detoxified alcoholics (Diana et al., 1993; Martinez et al., 2005; Volkow et al., 2007) and clinical studies have shown a significant association between alcoholism and overeating/obesity (Bulik et al., 2004; Thiele et al., 2003). This, combined with the fact that high ethanol preferenc is associated with low NAc DA levels, leads us to the overall hypothesis of this proposal, that prolonged consumption of highly palatable foods causes DA deficits that predisposes animals to high ethanol consumption and preference. PUBLIC HEALTH RELEVANCE: The idea that foods can be as addictive as drugs of abuse has been gaining much ground in both the biomedical research field as well as the general public. Furthermore, much evidence indicates several similarities in neurobiological mechanisms between overeating highly palatable foods as seen in obesity and excessive drugs use associated with addiction. The goal of this project is to determine how consumption of high-fat/high- carbohydrate foods leads to changes in the brain's reward circuitry that may act as a gateway to future alcohol and drug addiction.